The central hypothesis of this proposal is that GI hormones that regulate the growth of normal gut and pancreas may also regulate growth of some neoplasms (animal and human) arising from those tissues. We have found that gastrointestinal (GI) hormones affect growth by acting through specific hormone receptors on target tissue, but not all tissues respond to the same hormone in a similar fashion. Our studies are designed to determine which GI hormones stimulate and which GI hormones inhibit growth of these tissues, and to compare growth responses of normal and neoplastic tissue. We will study the physiologic role of endogenous GI hormones in maintenance of growth as well as in regeneration following injury or resection of the normal gut and pancreas. We will test the hypothesis that GI hormones play a role in development of spontaneous pancreatic cancers in transgenic mice. We determine whether by combining inhibitors of endogenous hormone release with hormone-receptor antagonists, we can achieve greater inhibition of growth. We plan to test the hypothesis that the mechanisms of action of GI hormones on growth include the following: different types of receptors for a given hormone might explain different growth responses of normal and neoplastic tumors to the same hormone; GI hormones act through regulation of protooncogene and ornithine decarboxylase-gene expression and polyamine biosynthesis. We have found that growth factors affect growth of some GI tumors; some growth factors are produced and secreted by normal and neoplastic GI tissues. We will test the hypothesis that GI hormones affect growth by releasing autocrine growth factors. We have established two unique functioning human endocrine cell lines growing in nude mice (a human gastrinoma, a human pancreatic carcinoid). We will study mechanisms of signal transduction by hormones and secretagogues in these human endocrine cells. The long-term goal of this project is to develop therapeutic strategies for the treatment of patients with gut and pancreatic cancers that employ hormone manipulation in a fashion similar to current therapeutic strategies used to treat breast and prostate cancer.